The immune system can exert powerful effects on nervous system function through release of paracrine factors from immunocompetent cells. Reports that: (I) procedures that reduce the recruitment or activation of macrophages reduce cell death in some experimentally induced brain pathologies, (ii) elevated levels of cytokines such as IL-I and TNF have been detected in the CNS of patients with diseases such as Alzheimer's and MDS, and (iii) cytokines have been implicated in some chronic pain syndromes, support the notion that perturbations in neural-immune communication can have a strong impact on mental and behavioral health. Unfortunately, the complexity of mammalian nervous and immune systems makes detailed cellular analysis of neural-immune interactions a challenging prospect A useful approach is to develop simpler preparations that share fundamental mechanisms with more complex systems. The marine mollusc Aplysia represents an ideal model system for such an approach because: (I) it has a relatively simple nervous system that has been well characterized at functional, cellular and molecular levels (ii) it shares with mammals similar basic cellular defensive responses to wounded-self or non-self, and (iii) preliminary studies by the PI have implicated cells of the cellular defense system (i.e. amebocytes) in the modulation of nervous system function in Aplysia. Specifically, the induction of a cellular defense reaction (resulting in the accumulation of amebocytes) in close proximity to sensory axons can produce a long-term increase in the excitability of those sensory neurons. Amebocytes also accumulate at a site of nerve crush which suggests the cellular defense system may play a role in mediating injury-induced plasticity. The overall goal of this proposal is to gain a better understanding of functional interactions between neural and immunological systems. The objective is to use both in vivo and in vitro preparations to test the general hypothesis that cells of the cellular defense system communicate with and modulate nervous system function in Aplysia. The specific aims are to: 1. Identify potential mediators of amebocyte-induced long-term sensory plasticity using the in vitro preparation. 2. Asses whether mediators found to influence sensory excitability in vitro.are present in Aplysia amebocytes. 3. Determine whether amebocytes cultured close to sensory axons in vitro can induce long-term sensory plasticity. 4. Determine whether factors present in Aplysia amebocytes can act acutely on peripheral nerves to influence axonal excitability. 5. Determine whether mediators found to influence sensory excitability can influence the regeneration of axons after injury. In vitro, mediators or amebocytes will be placed close to peripheral nerves. Amebocytes will be directed towards sensory axons in vivo by (i) crushing, or (ii) inducing foreign body reactions close to peripheral nerves. Standard intracellular recording techniques will be used to monitor neuronal function. Understanding fundamental mechanisms underlying neural-immune communication will facilitate the development of treatment strategies for immune-mediated neurological diseases.